A preferred administration of many drugs utilizes continuous or intermittent intravenous infusion.
For such administration and, generally, for parenteral administration of many medicaments, it is important to dilute the drug or medicament with a biologically compatible solution or vehicle. While the present description will be confined largely to the preparation of intravenous administration media, it should be understood that the invention is applicable to other administration systems in which a vehicle is intended to carry the medicament into the body and a sterile admixture of the medicament to the vehicle is to take place.
The most commonly used intravenous solutions for this purpose are 5 percent dextrose and 0.9 percent sodium chloride solutions, the latter being generally referred to as physiological saline.
These solutions are available in glass bottles or flexible containers of different sizes or volumes from different manufacturers.
The solutions are packaged in glass bottles usually under a vacuum and, because the flexible containers respond to atmospheric pressure, the contents thereof generally are under atmospheric pressure or pressureless if the atmospheric pressure is considered to be the reference point for measurement.
The drugs which must be diluted with such solutions can be packaged in dry powdered form or in a liquid form in glass vials. The glass vials themselves derive from many different manufacturers and may differ in size, volume and the pressure within the vial depending upon the production process or the packaging process of the manufacturer.
For example, the pressure within the vial may range from a deep vacuum of about 0.9 bar to a slight overpressure. Many of these vials can have an aluminum cap as governed by international or local standards, for example ISO-DIS 8362-3, with a rubber stopper of either 20 mm or 13 mm in diameter and constituting a self-sealing membrane which can be penetrated by a needle.
The state of the art in preparing a powdered drug in an intravenous form is to first inject a portion of the diluent into the drug vial. Since the powdered form of the medicament may be in lyophilized form, this step is referred to as a reconstitution. For this purpose, the needle of a syringe is pierced through the rubber stopper of the drug vial and the diluent is introduced in the vial by the syringe. After mixing and dissolution of the powder in the liquid, the solution is drawn back into the syringe and may be injected by the syringe through an appropriate port in the container in which the intravenous medium has been packaged. After mixing of the syringe solution with the packaged solution, the packaged mixture can be administered to the patient.
The preparation of intravenous solutions in this manner may cause risk to the patient.
For example, microorganisms can be introduced which can cause thromboflebitis and often fatal infection. Studies have indicated that 5 to 55 percent of intravenous solutions prepared in the above-described manner may be contaminated with microorganisms.
The chances of inadvertently introducing microorganisms into a solution increase with every step in the reconstitution and dilution process. It is important, therefore, to use a process having as few steps as is possible.
Mention may also be made of the fact that reconstitution and dilution processes may cause the introduction of pyrogens which can cause fever, particulate matter which can obstruct small arteries and veins and air which can cause the formation of lethal embolisms and can otherwise obstruct arteries and veins. The reconstitution or preparation of intravenous solutions can also be dangerous for the operator who performs the reconstitution or dilution. For example, the drug itself may be hazardous in the case of antineoplastics which are dangerous and hazardous even in small quantities when the exposure takes place over a period of time. Exposure to drugs through aerosols, needle leakage, drips and the like also may be hazardous. It is important, therefore, both for the patient and for the operator to be able to reconstitute the drug in an intravenous solution with a minimum number of steps, in a minimum amount of time and with a minimum danger of exposure of the operator to the diluted and nonreconstituted drug and to prevent inadvertent exposure of personnel to drugs while also preventing inadvertent introduction of foreign matter into the intravenous solution.
Several techniques have been developed to avoid problems of the type previously referred to. For example, a double-pointed needle has been developed. This needle, commonly known as a transfer needle, is pierced through the closure of the drug vial and then through the additive port of a flexible container or bag for the intravenous solution. The solution is forced from the container into the vial and then from the vial into the container by squeezing action. Any air that was in the container can then be forced into the vial. This technique and modifications thereof are described in U.S. Pat. No. 4,759,756.
In U.S. Pat. No. 4,614,267, a dedicated system is described in which the IV container and the drug vial are provided with mutually engaging means which secure the vial to the container. The vial can be screwed into the container and the rubber stopper can be removed to allow mixing of the IV solution the the drug.
Both of these systems are dependent on the presence of air. Air is needed, for example, to equalize the pressure of the total system with atmospheric pressure. In the absence of air, part of the reconstituted solution will remain trapped and will preclude complete delivery of a medicament dose to the patient. This can be detrimental.
In the case of transfer needles, the air comes from outside the system. When the drug vial is pierced with this needle, air is drawn into the drug vial and the pressure inside of the vial is equalized with atmospheric pressure. The advantage of this system is that the IV container can be essentially free from air. However, even if the reconstitution takes place in a sterile cabinet, there is always the danger of some contamination when the nonsterile air is introduced into the vial or from the vial into the IV solution.
In the system of U.S. Pat. No. 4,614,267, the air comes from within the system and IV containers for use in this system must, therefore, contain a certain volume of the air. This air is, of course, sterile and the sterility of the air is maintained. The system is not, however, satisfactory in many cases, because the amount of air required by the vial for suitable mixing will vary in accordance with the packaging pressure and the nature of the drug to be administered. For example, a vial with a vacuum of 0.9 bar and a volume of 100 ml will require 90 ml of air for atmospheric pressure balance while a vial packaged with a slight overpressure has to release air. Most drug vials fall somewhere within this range and it has been difficult to correlate the different vials with this latter system, especially where the system requires the use of proprietary vials under the control of a single licensor. Indeed, the IV containers for the latter system have generally had to have a large air volume to ensure equalization of pressure with the vials of the deepest vacuum and this may leave a volume of air in the container after reconstitution of 50 ml or more. The presence of any air can, of course, be detrimental to the organism because air introduced into the blood stream may occlude arteries and veins and cause tissue damage. It is generally thought that the introduction of 50 to 100 ml of air into the blood stream can be lethal.
Intravenous injection systems, therefore, must be carefully monitored for the presence of air and generally it is important to avoid the presence of any air in such systems.